Defective platelet responsiveness to thrombin and protease-activated receptors agonists in a novel case of gray platelet syndrome: Correlation between the platelet defect and the α-granule content in the patient and four relatives

Erica De Candia, A. Pecci, G. Ciabattoni, R. De Cristofaro, S. Rutella, Z. Yao-Wu, I. Lazzareschi, R. Landolfi, S. Coughlin, C. L. Balduini

Research output: Contribution to journalArticle

Abstract

Background: We report a novel case of gray platelet syndrome (GPS). A 14-year-old boy had bleeding diathesis, mild thrombocytopenia, giant platelets with severe defect of α-granule secretory proteins, myelofibrosis and splenomegaly. Methods and results: Platelet function studies showed a marked reduction of aggregation and Ca2+ mobilization by thrombin, protease-activated receptor 1 (PAR1)-activating peptide (AP) and PAR4-AP, PAR1 expression at 55% of normal levels, and a more than two hundred fold reduction of in vitro whole-blood thromboxane B2 (TXB2) production. Sequencing of coding regions of the PAR1 gene failed to show abnormalities. This patient was initially classified as a sporadic case of GPS, as electron microscopy failed to identify giant platelets and/or α -granule deficiency in his relatives. However, further studies on the father and three other relatives showed a relative lack of platelet α -granule proteins by immunofluorescence microscopy, a defective platelet response to PAR4-AP, and severely reduced in vitro whole-blood TXB2 production. On this basis, we suggest that in this family, GPS was transmitted in a dominant fashion with highly variable penetrance. Conclusions: Our study suggests that current diagnostic criteria fail to identify some patients with a mild GPS phenotype and that such patients might be identified by the methods cited above. It also better characterizes the pathogenesis of defective platelet responses to thrombin, and raises interesting questions on the correlation between abnormal PAR function and the lack of α-granule content in GPS.

Original languageEnglish
Pages (from-to)551-559
Number of pages9
JournalJournal of Thrombosis and Haemostasis
Volume5
Issue number3
DOIs
Publication statusPublished - Mar 2007

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Gray Platelet Syndrome
Proteinase-Activated Receptors
Thrombin
Blood Platelets
PAR-1 Receptor
Thromboxane B2
Peptides
Primary Myelofibrosis
Penetrance
Disease Susceptibility
Splenomegaly
Secretory Vesicles
Fluorescence Microscopy
Fathers
Thrombocytopenia
Electron Microscopy
Proteins
Hemorrhage
Phenotype

Keywords

  • Gray platelet syndrome
  • Platelet protease-activated receptors
  • Plateletα-granules
  • Thrombin receptors
  • Thromboxane biosynthesis

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Defective platelet responsiveness to thrombin and protease-activated receptors agonists in a novel case of gray platelet syndrome : Correlation between the platelet defect and the α-granule content in the patient and four relatives. / De Candia, Erica; Pecci, A.; Ciabattoni, G.; De Cristofaro, R.; Rutella, S.; Yao-Wu, Z.; Lazzareschi, I.; Landolfi, R.; Coughlin, S.; Balduini, C. L.

In: Journal of Thrombosis and Haemostasis, Vol. 5, No. 3, 03.2007, p. 551-559.

Research output: Contribution to journalArticle

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abstract = "Background: We report a novel case of gray platelet syndrome (GPS). A 14-year-old boy had bleeding diathesis, mild thrombocytopenia, giant platelets with severe defect of α-granule secretory proteins, myelofibrosis and splenomegaly. Methods and results: Platelet function studies showed a marked reduction of aggregation and Ca2+ mobilization by thrombin, protease-activated receptor 1 (PAR1)-activating peptide (AP) and PAR4-AP, PAR1 expression at 55{\%} of normal levels, and a more than two hundred fold reduction of in vitro whole-blood thromboxane B2 (TXB2) production. Sequencing of coding regions of the PAR1 gene failed to show abnormalities. This patient was initially classified as a sporadic case of GPS, as electron microscopy failed to identify giant platelets and/or α -granule deficiency in his relatives. However, further studies on the father and three other relatives showed a relative lack of platelet α -granule proteins by immunofluorescence microscopy, a defective platelet response to PAR4-AP, and severely reduced in vitro whole-blood TXB2 production. On this basis, we suggest that in this family, GPS was transmitted in a dominant fashion with highly variable penetrance. Conclusions: Our study suggests that current diagnostic criteria fail to identify some patients with a mild GPS phenotype and that such patients might be identified by the methods cited above. It also better characterizes the pathogenesis of defective platelet responses to thrombin, and raises interesting questions on the correlation between abnormal PAR function and the lack of α-granule content in GPS.",
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T2 - Correlation between the platelet defect and the α-granule content in the patient and four relatives

AU - De Candia, Erica

AU - Pecci, A.

AU - Ciabattoni, G.

AU - De Cristofaro, R.

AU - Rutella, S.

AU - Yao-Wu, Z.

AU - Lazzareschi, I.

AU - Landolfi, R.

AU - Coughlin, S.

AU - Balduini, C. L.

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N2 - Background: We report a novel case of gray platelet syndrome (GPS). A 14-year-old boy had bleeding diathesis, mild thrombocytopenia, giant platelets with severe defect of α-granule secretory proteins, myelofibrosis and splenomegaly. Methods and results: Platelet function studies showed a marked reduction of aggregation and Ca2+ mobilization by thrombin, protease-activated receptor 1 (PAR1)-activating peptide (AP) and PAR4-AP, PAR1 expression at 55% of normal levels, and a more than two hundred fold reduction of in vitro whole-blood thromboxane B2 (TXB2) production. Sequencing of coding regions of the PAR1 gene failed to show abnormalities. This patient was initially classified as a sporadic case of GPS, as electron microscopy failed to identify giant platelets and/or α -granule deficiency in his relatives. However, further studies on the father and three other relatives showed a relative lack of platelet α -granule proteins by immunofluorescence microscopy, a defective platelet response to PAR4-AP, and severely reduced in vitro whole-blood TXB2 production. On this basis, we suggest that in this family, GPS was transmitted in a dominant fashion with highly variable penetrance. Conclusions: Our study suggests that current diagnostic criteria fail to identify some patients with a mild GPS phenotype and that such patients might be identified by the methods cited above. It also better characterizes the pathogenesis of defective platelet responses to thrombin, and raises interesting questions on the correlation between abnormal PAR function and the lack of α-granule content in GPS.

AB - Background: We report a novel case of gray platelet syndrome (GPS). A 14-year-old boy had bleeding diathesis, mild thrombocytopenia, giant platelets with severe defect of α-granule secretory proteins, myelofibrosis and splenomegaly. Methods and results: Platelet function studies showed a marked reduction of aggregation and Ca2+ mobilization by thrombin, protease-activated receptor 1 (PAR1)-activating peptide (AP) and PAR4-AP, PAR1 expression at 55% of normal levels, and a more than two hundred fold reduction of in vitro whole-blood thromboxane B2 (TXB2) production. Sequencing of coding regions of the PAR1 gene failed to show abnormalities. This patient was initially classified as a sporadic case of GPS, as electron microscopy failed to identify giant platelets and/or α -granule deficiency in his relatives. However, further studies on the father and three other relatives showed a relative lack of platelet α -granule proteins by immunofluorescence microscopy, a defective platelet response to PAR4-AP, and severely reduced in vitro whole-blood TXB2 production. On this basis, we suggest that in this family, GPS was transmitted in a dominant fashion with highly variable penetrance. Conclusions: Our study suggests that current diagnostic criteria fail to identify some patients with a mild GPS phenotype and that such patients might be identified by the methods cited above. It also better characterizes the pathogenesis of defective platelet responses to thrombin, and raises interesting questions on the correlation between abnormal PAR function and the lack of α-granule content in GPS.

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